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A Seminiferous Tubule Squash Technique for the Cytological Analysis of Spermatogenesis Using the Mouse Model
Published on: February 6, 2018
BET bromodomain inhibitor JQ1 regulates spermatid development by changing chromatin conformation in mouse
Xiaorong Wang1, Mengmeng Sang1, Shengnan Gong1
1Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226001, PR China.
Abstract:
As a BET bromodomain inhibitor, JQ1 has been proven have efficacy against a number of different cancers. In terms of male reproduction, JQ1 may be used as a new type of contraceptive, since JQ1 treatment in male mice could lead to germ cell defects and a decrease of sperm motility, moreover, this effect is reversible. However, the mechanism of JQ1 acting on gene regulation in spermatogenesis remains unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) on mouse testes treated with JQ1 or vehicle control to determine the transcriptional regulatory function of JQ1 in spermatogenesis at the single cell resolution. We confirmed that JQ1 treatment could increase the numbers of somatic cells and spermatocytes and decrease the numbers of spermatid cells. Gene Ontology (GO) analysis demonstrated that differentially expressed genes which were down-regulated after JQ1 injection were mainly enriched in "DNA conformation change" biological process in early developmental germ cells and "spermatid development" biological process in spermatid cells. ATAC-seq data further confirmed that JQ1 injection could change the open state of chromatin. In addition, JQ1 could change the numbers of accessible meiotic DNA double-stranded break sites and the types of transcription factor motif that functioned in pachytene spermatocytes and round spermatids. The multi-omics analysis revealed that JQ1 had the ability to regulate gene transcription by changing chromatin conformation in mouse spermatogenesis, which would potentiate the availability of JQ1 in male contraceptive.
Insights
JQ1, a BET bromodomain inhibitor, impacts male fertility by altering gene regulation in spermatogenesis. This study reveals JQ1 affects chromatin accessibility and gene expression, offering potential for male contraceptives.
Area of Science:
- Reproductive Biology
- Molecular Biology
- Genetics
Background:
- JQ1 is a BET bromodomain inhibitor with demonstrated anti-cancer effects.
- JQ1 shows potential as a reversible male contraceptive due to observed germ cell defects and reduced sperm motility in mice.
- The precise mechanism by which JQ1 regulates gene expression during spermatogenesis is not fully understood.
Purpose of the Study:
- To elucidate the transcriptional regulatory mechanisms of JQ1 in mouse spermatogenesis at a single-cell level.
- To investigate the impact of JQ1 on gene expression and chromatin accessibility during male germ cell development.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was employed on mouse testes treated with JQ1 or a vehicle control.
- Gene Ontology (GO) analysis was performed on differentially expressed genes.
- Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) was utilized to assess chromatin accessibility.
Main Results:
- JQ1 treatment altered the cellular composition of testes, increasing somatic cells and spermatocytes while decreasing spermatids.
- Down-regulated genes after JQ1 treatment were enriched in "DNA conformation change" and "spermatid development" pathways.
- JQ1 modified chromatin accessibility, meiotic DNA double-strand break sites, and transcription factor motif activity in specific germ cell stages.
Conclusions:
- JQ1 regulates gene transcription in mouse spermatogenesis by altering chromatin conformation.
- These findings highlight JQ1's potential as a male contraceptive agent by modulating key regulatory processes in sperm development.
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